This RO3 application is in response to PA-99-049 and Research Objectives number 7 (Sensory and Motor Processing), number 13 (Genetic, Cellular and Biochemical Basis of Functional Senescence), and number 18 (Animal Models of Aging). The goal of this research is to understand the relationship between target- derived neurotrophins and aging of the cutaneous sensory system. Aging of the cutaneous sensory system is associated with increased thresholds for tactile, vibratory, and thermal stimuli. These functional deficits cannot be explained by simple neuronal loss however, since neuron number does not significantly decline in the aged sensory ganglia. Decreased sensory function is associated with axonal loss and end organ degeneration in the periphery which could be due to reduced trophic support from the peripheral target-tissue. To test this hypothesis, the expression of the NT3 and BDNF neurotrophin growth factors in aged cutaneous tissue will be measured. These neurotrophins will be examined because of their known effects on the Merkel and Meissner type sensory endings. Expression will be measured on the mRNA and protein level using RT-PCR and ELISA analysis, respectively. To provide a model system to determine whether enhanced neurotrophin expression by the skin can improve sensory ending morphology in the aged animal, transgenic mouse lines will be established the inducibly express either NT3 or BDNF in the epidermis. Expression will be targeted to basal keratinocytes of the epidermis using the K14 keratin promoter and enhancer region and regulated by the tamoxifen-inducible Cre-ER fusion protein system. Following induction, measures of sensory end organ size, number, and axonal integrity will be made using immunolabeling analysis. These studies will advance our understanding of age- related sensory dysfunction by determining: 1) whether neurotrophic factor synthesis in the skin is reduced during aging, and 2) whether enhancement of neurotrophic factor synthesis in the skin can reverse age-related sensory deficits. The findings of this study should be applicable to other sensory systems in which target-derived support has an essential role in sensory ending maintenance.